A fundamental step to cellular DNA replication and transcription processes is associated with the separation of DNA helical strands. DNA helical structure of eukaryotic cells dictate specific topological properties which may lead to problems that a cellular apparatus must resolve in order to use genetic material as a template for cellular replication processes. Eukaryotic DNA strands, organized into chromatin by chromosomal proteins, are constrained such that those strands cannot unwind without the aid of topology altering enzymes. In light of this, it has long been recognized that advancement of a transcription or replication complex along a DNA helix would be facilitated by a swivel point that would relieve conformational torsional strain generated during such processes.
Topoisomerases are important enzyme components in cellular functions capable of altering DNA topology in eukaryotic cells and cell proliferation processes. Topoisomerases alter the linking number of DNA (i.e., equal to the number of times that a DNA strand winds in right handed helical axis direction) by catalyzing a three step process: the cleavage of one or both strands of DNA, the passage of a segment of DNA through such break(s), and the resealing of the DNA break.
Two topoisomerase classes have been associated with eukaryotic cells: Type I topoisomerase and type II topoisomerase. Both topoisomerases type I and type II play important roles in DNA replication, transcription, and recombination. In general, inhibition of topoisomerase I has been the major target of oncologic, anti-neoplastic, anti-viral agents, etc. Inhibition of topoisomerase II is the major target of important commercial oncolytic agents (e.g., etoposide, doxorubicin and mitoxantrone) as well as other oncolytic agents still undergoing development.
An example of a class of DNA topoisomerase I inhibiting compounds include camptothecin and its corresponding analog or congener derivatives. Camptothecin is a water-insoluble, cytotoxic alkaloid produced by plants, such as Camptotheca accuminata trees indigenous to China and Nothapodytes foetida trees indigenous to India. Camptothecins generally (such as topotecan) are discussed in Cancer Chemotherapy and Biotherapy (see, pp. 463-484; 2nd edition, Eds. Bruce A. Chabner and Dan L. Longo, Lippincott-Raven Publishers, Philadelphia, 1996). Examples of camptothecin analog derivatives include topotecan, irinotecan, and 9-aminocamptothecin.
U.S. Pat. No. 5,004,758 discloses topotecan, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)dione monohydrochloride (also known as 9-dimethylaminomethyl-10-hydroxycamptothecin, etc.), as depicted by the following chemical structure:

Topotecan also is listed in The Merck Index (see 12th Ed., monograph no. 9687, Merck & Co., Inc., 1996). Clinical tests have shown that topotecan demonstrates efficacy against several solid tumor cancers, particularly ovarian cancer, esophageal cancer, and non-small cell lung carcinoma in humans.
Hycamtin® (sold by GlaxoSmithKline, Brentford, UK), which contains topotecan hydrochloride, is formulated as a lyophilized mixture, suitable for intravenous administration after reconstitution. Typically, this product is administered by medical professionals in a hospital, clinic or doctor's office setting. This dosing requires patients to travel to such facilities, sometimes daily, for treatment. It would be desirable to develop a pharmaceutical form of topotecan hydrochloride that could be readily and safely manufactured and would be useful in the preparation of a pharmaceutical composition that could be administrable by patients in any setting, e.g. at home. Generally, such self-administrable pharmaceutical forms are solid, orally administrable forms.